Structure-activity relationship in the 3-iodo-4-phenoxypyridinone (IOPY) series: The nature of the C-3 substituent on anti-HIV activity

Article abstract of DOI:10.1016/j.bmcl.2006.10.082

As part of a systematic SAR study on the 3-iodo-4-phenoxypyridinone 3 (IOPY) type non-nucleoside reverse transcriptase inhibitors, the analogues 4a-4z bearing different C-3 substituents were synthesized and evaluated for their anti-HIV activity against wild-type HIV-1 and four of the principal HIV mutant strains (K103N, Y181C, Y188L, and I100L). The results show that the 3-vinyl analogue 4j is the only compound which displays anti-HIV activity comparable to IOPY 3, and in this respect represents a possible back-up to this lead molecule.

Full text of DOI:10.1016/j.bmcl.2006.10.082

Bioorganic & Medicinal Chemistry Letters 17 (2007) 712–716
Structure–activity relationship in the 3-iodo-4-phenoxypyridinone
(IOPY) series: The nature of the C-3 substituent
on anti-HIV activity
Abdellah Benjahad,a,* Said Oumouch,a Jeroˆme Guillemont,b Elisabeth Pasquier,b
Dominique Mabire,b Koen Andries,c Chi Hung Nguyena,* and David S. Griersona
aUMR 176 CNRS-Institut Curie, Laboratoire de Pharmacochimie, Section de Recherche, Batiment 110,
Centre Universitaire, 91405 Orsay, France
bJohnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry Department,
Campus de Maigremont BP315, Val de Reuil, France
cJohnson & Johnson Pharmaceutical Research and Development, Virology Drug Discovery, Tumhoutseweg 30 B-2340 Beerse, Belgium
Received 15 September 2006; revised 25 October 2006; accepted 26 October 2006
Available online 1 November 2006
Abstract—As part of a systematic SAR study on the 3-iodo-4-phenoxypyridinone 3 (IOPY) type non-nucleoside reverse transcrip-
tase inhibitors, the analogues 4a–4z bearing different C-3 substituents were synthesized and evaluated for their anti-HIV activity
against wild-type HIV-1 and four of the principal HIV mutant strains (K103N, Y181C, Y188L, and I100L). The results show that
the 3-vinyl analogue 4j is the only compound which displays anti-HIV activity comparable to IOPY 3, and in this respect represents
a possible back-up to this lead molecule.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The 3-iodo-4-phenoxypyridinone 3 (IOPY) is represen-
tative of a new family of pyridinone based non-nucleo-
side reverse transcriptase inhibitors (NNRTI’s) which
O
O
are highly active in vitro against a broad panel of
HIV-1 mutant strains encountered in AIDS patients.1
Compound 3, obtained in high yield through reaction
of 3,5-dimethyl(dichloroiodo)benzene with the 4-
hydroxypyridinone 2 (Scheme 1), was originally synthe-
sized with the idea that the iodo substituent could be
used as a convenient vehicle to incorporate widely differ-
ing functionality at the C-3 position of the pyridinone
ring. As reported in this communication, we have ex-
plored this option to see whether new phenoxypyridi-
none analogues could be identified having an anti-HIV
activity profile superior to that for the lead molecule 3.
A series of 26 new 3-substituted phenoxypyridinone
analogues 4a–4z have been synthesized (Schemes 1–4)
and evaluated for their anti-HIV activity against wild-
type HIV-1 (Table 1) and four of the principal HIV
R
CO Et
2
1. POCl , 50%
3
HN
HN
_
+
2.
OH
O
O K
1 R = CO Et
2 R = H
2
a
4a
DMF, reflux
5h, 94%
Cl
Cl
I
91%
(ref 1)
O
I
HN
O
Keywords: NNRTI; Pyridinone; IOPY; Anti-HIV.
*
Corresponding authors. Tel.: +33 1 6986 7115; fax: +33 1 6907
5381; e-mail addresses: Abdellah.Benjahad@curie.u-psud.fr; chi.hung@
curie.u-psud.fr
3
Scheme 1.
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.082

A. Benjahad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 712–716
713
mutant strains (K103N, Y181C, Y188L, and I100L)
which confer resistance to the NNRTI’s. Selected com-
pounds were further evaluated against the two double
mutant strains 100I + 103N and 103N + 181C.
O
O
R
O
R
O
HN
a
HN
f
4a
To obtain analogue 4a with an ester functionality at
C-3, it proved judicious to work with pyridinone 1
(Scheme 1). Treatment of this material with POCl3, fol-
lowed by reaction of the derived 4-chloropyridinone
intermediate with potassium 3,5-dimethylphenate in
refluxing DMF, provided the target ester in 47% yield
for the two steps.1,2 Continuing with 4a (Scheme 2),
the ester function was reduced using LiAlH4 (THF,
20 ꢁC, 4 h, 60%) to give alcohol 4b. Oxidation of 4b
using MnO2 (CH2Cl2, rt, 18 h) then furnished aldehyde
5 (90% yield). This product was subsequently used to
prepare oxime 4c (NH2OH, EtOH, rt, 2 h, 52%) and
acrylate 4d (Ph3P@CHCO2Et, THF, Rfx, 4 h, 65%).
Selective reduction of the ester motif in 4d (DiBAl-H,
CH2Cl2, ꢀ78 ꢁC, 60%) gave the C-3 allylic alcohol con-
taining analogue 4e.
h
4b R = CH OH
4f R = H
2
b
g
5
R = CHO
4g R = Br
4h R = Cl
c
d
N
OH
CO Et
4c R =
4d R =
2
6
R = CO H
2
e
i
OH
4e R =
4i = CONMe
2
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 20 ꢁC, 4 h,
60%; (b) MnO2, CH2Cl2, 20 ꢁC, 18 h, 90%; (c) NH2OH, EtOH, rt, 2 h,
52%; (d) Ph3P@CHCO2Et, THF, reflux, 4 h, 65%; (e) DiBAl-H,
CH2Cl2, ꢀ78 ꢁC, 60%; (f) 2N HCl, reflux, 18h, 86%; (g) NBS 94% (for
4g) or NCS 90% (for 4h), HOAc/EtOAc 1:1, 20 ꢁC, 1 h; (h) 3 N HCl,
20 ꢁC, 1 h, 78%; (i) Me2NH, DCC, HOBT, Et3N, CH2Cl2, rt, 8 h, 77%.
Alternatively, treatment of 4a with aqueous acid at re-
flux effected ester hydrolysis and decarboxylation giving
the pydridinone 4f lacking substitution at C-3. Reaction
of this aryloxypyridinone intermediate with N-bromo-
O
O
I
R
O
a or b or c or d or e
HN
HN
succinimide
produced the 3-bromo analogue 4g3
O
(94%) of lead compound 3, and the corresponding reac-
tion with NCS gave the 3-chloro compound 4h (90%).
Under mild hydrolysis conditions compound 4a was
converted to acid 6, providing the opportunity to pre-
pare the dimethylamide 4i (77%).
3
f
4q R = Et
4r R =
4j R =
4k R =
4o R =
4p R = S(CH ) CONH
Ph
g
2 2
2
O
h
IOPY 3, itself, was engaged in Pd(0) coupling reactions
with the requisite tributyltin or boronate reagents to
prepare the C-3 vinyl (4j),4 2-furyl (4k), propenyl (4l),
3-thienyl (4m), b-iodovinyl (4n), and phenylethynyl
(4o) compounds, as well as the extended chain amide
4p5 [(i) Bu3SnS(CH2)2CO2Et, Pd(0), DMF, 120 ꢁC,
72 h, 50%; (ii) ester to acid (KOH, EtOH, H2O, reflux,
2 h, 96%), and (iii) acid to amide (SOCl2 then NH3,
30% yield)] (Scheme 3). The C-3 ethyl analogue 4q was
obtained by catalytic hydrogenation of the double bond
in 4j, and the cyclopropane analogue 4r was obtained by
treatment of this vinyl analogue with CH2I2 and Et2Zn
(57% yield).6 In metal–halogen exchange reactions
(n-BuLi, THF, ꢀ78 ꢁC, MeSSMe or EtSSEt 30–35%)
compound 3 was converted to the 3-methylthio analogue
4s7 or to the homologous 3-ethylthio pyridinone 4t.8
S-Oxidation of 4s provided the corresponding sulfoxide
4u in excellent yield. By simply heating 3 with thiophenol
(K2CO3 in DMF, CuCl, 140 ꢁC, 11%) overnight the
SPh analogue 4v was also prepared. In a similar fashion,
heating 3 in the presence of NaOMe/CuI or CuCN led
to formation of the 3-OMe and 3-CN substituted
analogues 4w9 and 4x, respectively.
4s R = SMe
4t R = SEt
4v R = SPh
4w R = OMe
4x R = CN
4u
R = S(O)Me
Me
4l R =
4m R =
S
I
4n R =
Scheme 3. Reagents and conditions: (a) RB(OH)2 or RSnR03, Pd(0),
DMF or DME reflux for 4j, 4k, 4l, 4m, 4n, 4o and 4p; (b) BuLi, THF,
ꢀ78 ꢁC, MeSSMe for 4s or EtSSEt for 4t; (c) thiophenol, DMF,
K2CO3, reflux for 4v; (d) 30% NaOMe in MeOH, CuI, DMF, 90 ꢁC,
48 h, 29% for 4w; (e) CuCN, Py, reflux for 4x; (f) H2, Pd/C; (g) CH2I2,
Et2Zn, CF3CO2H, CH2Cl2, 20 ꢁC, 18h, 57%; (h) m-CPBA, CH2Cl2.
2
OR
O
1
R
R
O
3
c or d
N
a or b
HN
4a
O
1
2
7 R = I, R = PMB
4y R = CF3
4z R = i-Pr
1
2
8 R = CO Me, R = Me
2
For preparation of 4y and 4z, it was first necessary to
O-alkylate IOPY 3 and ester 4a. This was readily
achieved under Mitsunobu conditions.10 Subsequent
reaction of the 2-O-para-methoxybenzyl (O-PMB)
pyridine 7 with FSO2CF2CO2Me, CuI in DMF at
80 ꢁC provided access to the target 3-CF3 analogue 4y
Scheme 4. Reagents and conditions: (a) DEAD, PPh3, 4-MeOBnOH,
THF, 20 ꢁC, 18h, 58% for 7 from 3; (b) DEAD, PPh3, MeOH, THF,
20 ꢁC, 18 h, 54% for 8 from 4a; (c) FSO2CF2CO2Me, CuI, DMF,
80 ꢁC, 24 h, 87% for 4y from 7; (d) i—MeLi (3 equiv), THF, 0 ꢁC 1 h
then reflux 18 h then; ii—Ac2O, reflux, 18 h, 58% (2 steps); iii—H2, Pd/
C then 3 N HCl, reflux, 18 h, 40% for 4z from 8.

714
A. Benjahad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 712–716
in 87% yield.11 Reaction of the O-methylpyridine 8 with
two equivalents of MeLi resulted in double addition to
the ester function giving the expected tertiary alcohol
intermediate, which was converted to the 3-isopropyl
compound 4z in three steps (acetylation/elimination
(Ac2O, reflux), reduction (H2, Pd/C), and O-demethyla-
tion (3N HCl, reflux)).
C-3, and the C-3 cyano substituted analogue 4x are,
respectively, 300- and 63-fold less active than the more
bulky or globular iodo substituted lead compound 3.
The chloro substituted analogue remains slightly, but
measurably less active than 3, whereas the bromo substi-
tuted analogue is essentially equipotent to this lead com-
pound. The 3-SMe (4s), OMe (4w), CF3 (4y), vinyl (4j),
and Et (4q) substituted compounds also display activi-
ties very close to IOPY 3. From these data it would ap-
pear that these substituents, which are similar in their
bulk or size, are optimal in terms of their interaction
within the hydrophobic pocket of RT. Indeed, for the
larger or more extended SEt analogue 4t, vinyl iodide
4n the propenyl substituted compound 4l, and the phe-
nylacetylene derivative 4o a decrease in activity is ob-
served. Indeed, compound 4o is inactive. However, this
view is lacking in precision as compound 4v substituted
by a SPh motif is highly active, as is compound 4p which
can be looked upon as an analogue of 4t in which a po-
lar amide function is added at the end of the linear
chain. Heterocyclic motifs at C-3, as in the furan ana-
logue 4k and thiophene 4m as well as certain small polar
substituents at C-3 (cf. 4n, 4u, and to a lesser extent 4c),
also interact favorably with the hydrophobic pocket, but
As the in vitro (cell based assay) anti-HIV12 data show
(Table 1), 9 of the 26 analogues prepared displayed
activity in the IC50 = 1–10 nM range against wild-type
HIV-1, and an additional 5 compounds were active be-
low the cut-off point of IC50 = 20 nM, the upper limit
fixed by us for further evaluation to be considered (listed
in alphabetical order; analogues with IC50 LAI
strain > 20 nM are presented separately at the bottom
of Table 1).
These data indicated that for wild-type RT the shape,
volume, and the polar nature of the substituent at C-3
are important for activity. In the direction of increasing
volume, this effect can be seen by comparing the IC50
values for compounds 4f (3-H), 4x (CN), 4h (Cl), 4g
(Br), and 3 (I). Compound 4f, lacking substitution at
Table 1. Activity (IC50, nM) versus HIV-112 for compounds 4a–z
O
R
O
HN
Compound
R
LAI
19.9
SIa
5012
103N
181C
188L
100I
100I + 103N
63.1
103N + 181C
158
4b
4g
4h
CH2OH
Br
Cl
1.99
90,119
10,000
39.8
19.9
63.1
100
631
398
6.3
3.1
31.6
6.3
4j
6309
126
3.1
19.9
12.5
200
4k
4p
15.8
12.5
O
S
1995
316
794
2511
158
CONH
2
4q
4r
4s
4u
Et
3.1
6.3
3162
1259
39.8
199
39.8
158
63.1
12.5
39.8
19.9
158
125
SMe
1.99
25,119
6309
31.6
31.6
63.1
31.6
O
S
15.8
4v
SPh
OMe
CF3
10.0
2.5
5012
39,811
12,589
794
158
158
50.1
794
794
199
125
1584
316
1584
501
4w
4y
79.4
12.5
31.6
31.6
3.1
4z
3
19.9
5012
9000
39.8
39.8
19.9
31.6
50.1
158
12.5
I
1.25
1.0
3.16
39.8
6.31
3.98
19.9
39.8
39.8
EFVb
10,000
1.99
1,000
(continued on next page)

A. Benjahad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 712–716
715
Table 1 (continued)
IC50 LAI (nM)
IC50 LAI (nM)
4a
4c
4d
4e
4f
4i
R = CO2Et
631
4l
39.8
50.1
100
R =
R =
OH
31.6
6310
63.1
398
4m
4n
4o
4t
R =
N
S
O
R
HN
I
CO Et
R =
R =
2
R =
O
15,848
125
R =
OH
R = H
R = SEt
R = CN
R = CONMe2
5020
4x
79.4
a Selectivity index or ratio of CC50 to IC50 relative to LAI (fold).
b EFV, efavirenz.
5 mmol) in EtOH (15 mL) was heated at reflux for 10 min.
The solvent was then removed and the residue was
dissolved in DMF (15 mL) and 3-carbethoxy 4-chloro-5-
ethyl-6-methyl-2(1H)-pyridinone2 (244 mg, 1 mmol) was
added. After heating at reflux for 5 h, water (30 mL) was
added and the mixture was extracted with EtOAc (3·
20 mL). The combined organic layers were washed with
brine (15 mL), dried over MgSO4, and concentrated.
Silica-gel column chromatography of the residue
(CH2Cl2/EtOH; 97:3) provided 4a as yellow solid
(310 mg, 94%): mp 202–204 ꢁC 1H NMR (CDCl3) d
13.15 (1H, br s), 6.66 (1H, s), 6.53 (2H, s), 3.95 (2H, q,
J = 7.0 Hz), 2.37 (3H, s), 2.34 (2H, q, J = 7.2 Hz), 2.25
(6H, s), 0.99 (6H, m). Step 2: compound 4a (200 mg,
0.61 mmol) was dissolved in 2 N aqueous HCl (10 mL)
and heated at reflux for 18 h. After cooling to room
temperature, the mixture was poured into ice water,
basified using NH4OH (28%), and extracted with EtOAc
(3· 20 mL). The combined organic layers were dried over
MgSO4 and evaporated to give compound 4f (133 mg,
86%) as a white solid which was dissolved in HOAc (2 mL)
and EtOAc (2 mL). At room temperature, and in the dark,
N-bromosuccinimide (44 mg, 0.19 mmol) was added in
one portion. After stirring for 1 h at room temperature,
the mixture was poured into water (5 mL) and the pH of
the solution was adjusted to ca. 7 with NH4OH (28%). The
combined organic layers obtained by extraction with
EtOAc (3· 10 mL) were dried over MgSO4 and evaporat-
ed to give a solid residue. Compound 4g was obtained as
white microcrystals (61 mg, 94%) after silica-gel flash
a considerable loss in activity was observed for the ester
analogue 4a, the corresponding dimethylamide 4i, and
the conjugated ester analogue 4d.
These results on wild-type HIV suggest that the eight
analogues 4g, 4h, 4j, 4q, 4r, 4s, 4w, and 4y are viable
alternatives to IOPY 3 for lead development. However,
further evaluation of these compounds against the four
mutant strains brought to light a number of limitations.
Indeed, with the exception of the 3-vinyl analogue 4j all
these analogues were less active than IOPY 3 against
one or several of the mutant strains. This may result
from a weaker interaction with Gly 190 and/or Val
189, which are a key feature in the binding of the iodine
atom in 3,13 and/or from steric clashes with the 181C
and 188L residues as observed in related non-nucleoside
RT inhibitors.14 Noteworthy is the increased sensitivity
of the C-3 vinyl analogue 4j over IOPY 3 and the clini-
cally used reference compound efavirenz against the
important Y188L mutant. However, a diminished level
of sensitivity relative to the two control compounds
was observed for the double mutant K103N + Y181C.
Globally, IOPY 3 remains the most attractive pyridi-
none based NNRTI developed to date. This does not
preclude, however, that in subsequent in vivo evaluation
the vinyl analogue 4j, or one of the other C-3 modified
4-aryloxypyridinones, may prove attractive for further
development.
1
chromtography (CH2Cl2/EtOH; 98:2): mp 240–242 ꢁC H
NMR (CDCl3) d 13.45 (1H, br s), 6.68 (1H, s), 6.47 (2H,
s), 2.44 (3H, s), 2.35 (2H, q, J = 7.3 Hz), 2.26 (6H, s), 0.99
(3H, t, J = 7.3 Hz) MS (ES): m/z 334.1 and 336.1 (MꢀH).
4. 4-(3,5-Dimethylphenoxy)-3-ethenyl-5-ethyl-6-methyl-2(1H)-
pyridinone 4j. Step 1: dichloro-3,5-dimethyliodobenzene
(obtained by the procedure described by Lucas et al. (Org.
Synth. 1955, 3, 482)) (3.75 g; 12.4 mmol) was suspended in
water (50 mL) containing sodium carbonate (1.31 g;
12.4 mmol) and stirred for 30 min at room temperature.
To this mixture a solution of 5-ethyl-6-methyl-4-hydroxy-
2(1H)-pyridinone 2 (see Ref. 2) (1.9 g; 12.4 mmol) in water
(50 mL) containing also sodium carbonate (1.31 g;
12.4 mmol) was added. After stirring for l h at 20 ꢁC, the
References and notes
1. Benjahad, A.; Guillemont, J.; Andries, K.; Nguyen, C. H.;
Grierson, D. S. Bioorg. Med. Chem. Lett. 2003, 13, 4309.
2. Dolle, V.; Fan, E.; Nguyen, C. H.; Aubertin, A.-M.; Kirn,
A.; Andreola, M. L.; Jamieson, G.; Tarrago-Litvak, L.;
Bisagni, E. J. Med. Chem. 1995, 38, 4679.
3. 3-Bromo-4-(3,5-dimethylphenoxy)-5-ethyl-6-methyl-2(1H)-
pyridinone 4g. Step 1: following the procedure described by
Bishop et al. (J. Chem. Soc. 1952, 437), a mixture of 3,5-
dimethylphenol (610 mg, 5 mmol) and KOH (280 mg,

716
A. Benjahad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 712–716
precipitate was filtered off, washed with water, dried
8. Kobayashi, K.; Koyama, E.; Namatame, K.; Kitaura, T.;
Kono, C.; Goto, M.; Obinata, T.; Furukawa, N. J. Org.
Chem. 1999, 64, 3190.
thoroughly under vacuum at room temperature, and then
suspended in DMF (20 mL). The mixture was refluxed for
l h and the solvent was evaporated under vacuum. Purifi-
cation by silica-gel flash chromatography (CH2Cl2/EtOH;
98:2) provided 4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-6-
methyl-2(1H)-pyridinone 3 (4.3 g, 91%) as colorless micro-
crystals; mp 240 ꢁC. 1H NMR (CDCl3) d 13.35 (1H, br s), 6.68
(1H, s), 6.46 (2H, s), 2.44 (3H, s), 2.35 (2H, q, J = 7.3 Hz), 2.26
(6H, s), 0.96 (3H, t, J = 7.2 Hz). Step 2: to a mixture of
compound 3 (1.0 g, 2.6 mmol) and palladium tetrakistriphe-
nylphosphine (300 mg, 10% mol) in toluene (15 mL) at room
temperature was added tributyl(vinyl) tin (0.91 mL,
3.1 mmol), and the mixture was refluxed for 12 h. Water
(8 mL) was then added and the aqueous layer was extracted
with CH2Cl2 and the combined organic layers were dried over
MgSO4. Thesolvent wasremovedand the residue waspurified
by flash chromatography (neutral alumina; CH2Cl2/EtOH
(98:2)) to give the title compound 4j as colorless microcrystals
(520 mg, 70%); mp 208 ꢁC. 1H NMR (CDCl3) d 12.28 (1H, br
s), 6.40–6.70 (4H, m), 5.32 (1H, dd, J = 10.3 and 4.4 Hz), 3.73
(3H, s),. 2.39 (3H, s), 2.20–2.35 (8H, m), 0.97 (3H, t,
J = 7.4 Hz) MS (ES): m/z 282.2 (MꢀH).
9. 4-(3,5-Dimethylphenoxy)-5-ethyl-3-methoxy-6-methyl-2(1H)-
pyridinone 4w. To a solution of copper(I) iodide (2 g,
10.53 mmol) in DMF (15 mL) was added at room
temperature iodopyridinone 3 (1.5 g, 3.9 mmol) then
sodium methoxide (7.5 mL, 30% w/w solution in MeOH).
The mixture was stirred at 90 ꢁC in a oil bath for 48 h,
followed by addition of H2O and extraction with EtOAc.
The combined organic layers were dried (MgSO4) and
concentrated. The residue was silica-gel column chro-
matographed (CH2Cl2/i-PrOH; 97:3) as the eluent. Crys-
tallization from acetone/MeOH (80/20) gave pyridinone
1
4w (0.32 g, 29%) as a white solid: mp 178 ꢁC. H NMR
(CDCl3) d 13.1 (1H, br s), 6.69 (1H, s), 6.56 (2H, s), 3.73
(3H, s), 2.38 (5H, m), 2.29 (6H, s), 1.04 (3H, t, J = 7.4 Hz)
Anal. Calcd for (C17H21NO3): C, 71.06; H, 7.37; N, 4.87.
Found: C, 70.76; H, 7.42; N,4.82.
10. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Castro, B. R. Org.
React. 1983, 29, 1.
11. Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun.
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5. Dickens, M. J.; Gilday, J. P.; Mowlem, T. J.; Widdowson,
D. A. Tetrahedron 1991, 47, 8621.
6. Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39,
8621.
12. All compounds were tested for potency (IC50, nM) to
achieve 50% protection of MT-4 cells from HIV-1 cyto-
pathicity as determined by the MTT method: Pauwels, R.;
Balzarini, J.; Baba, M.; Snoek, R.; Schols, D.; Herdewijn,
P.; Desmyter, J.; De Clercq, E. J. Virol. Methods 1988, 20,
309, Unless noted otherwise, the LAI strain of HIV-1 was
the infecting virus. Other infecting mutant (in the reverse
transcriptase) strains of virus are characterized in the tables
by the mutated amino acid position and the one letter codes.
For instance, 181C refers to replacement of tyrosine at
position 181 with cysteine. All determinations are average
values for three or more tests.
13. Himmel, D. M.; Das, K.; Clark, A. D., Jr.; Hughes, S. H.;
Benjahad, A.; Oumouch, S.; Guillemont, J.; Coupa, S.;
Poncelet, A.; Csoka, I.; Meyer, C.; Andries, K.; Nguyen, C.
H.; Grierson, D. S.; Arnold, E. J. Med. Chem. 2005, 48, 7582.
14. Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato,
M.; Stuart, D. I.; Stammers, D. K. J. Med. Chem. 1999,
42, 4500.
7. 4-(3,5-Dimethylphenoxy)-5-ethyl-6-methyl-3-methylsulfanyl-
2(1H)-pyridinone 4s. n-Butyllithium (1.6 M in hexane,
2.44 mL, 3.9 mmol) was added dropwise at ꢀ78 ꢁC to a
solution of 3 (575 mg, 1.5 mmol) in THF (25 mL) under
nitrogen. The mixture was stirred at ꢀ78 ꢁC for 20 min. and
dimethyl disulfide (0.67 mL, 7.5 mmol) in THF (3 mL) was
added dropwise. The mixture was stirred at room temper-
ature for 2 h and methanol (20 mL) was added. The mixture
as then concentrated under vacuum and the residue was
purified by silica-gel flash chromtography (CH2Cl2/EtOH;
97:3) providing compound 4s as a yellow solid (156 mg,
35%) mp 186–188 ꢁC 1H NMR (CDCl3) d 13.33 (1H, br s),
7.25 (1H, s), 6.44 (2H, s), 2.42 (3H, s), 2.34 (3H, s), 2.31
(2H, q, J = 7.3 Hz), 2.25 (6H, s), 0.98 (3H, t, J = 7.3 Hz)
MS (ES): m/z 302.1 (MꢀH).